Background: Knee osteoarthritis (OA) is a leading cause of pain and disability worldwide, often impairing mobility and quality of life. Conventional management strategies include physical therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), and intra-articular injections of corticosteroids or hyaluronic acid. However, such modalities may not adequately halt disease progression or provide sustained symptomatic relief. Platelet-Rich Plasma (PRP), an autologous product enriched with platelets and growth factors, has emerged as a promising therapeutic option to potentially stimulate tissue repair and modulate inflammation in the osteoarthritic joint. Evidence on large-scale efficacy in moderate knee OA remains limited. Methods: This randomized controlled trial enrolled 1000 patients with radiographically confirmed Grade II–III knee OA (Kellgren–Lawrence classification). Participants were randomly assigned to either receive three intra-articular injections of leukocyte-poor PRP (n = 500) at monthly intervals or an equivalent volume of normal saline (n = 500) as a control. All patients followed a standardized physiotherapy regimen and were evaluated at baseline, 3 months, and 6 months for changes in pain (Visual Analog Scale, VAS), function (Western Ontario and McMaster Universities Osteoarthritis Index, WOMAC), and overall knee performance (Knee Society Score, KSS). Adverse events and patient satisfaction rates were also recorded. Results: At 6 months, the PRP group demonstrated significantly greater improvements in VAS (−3.2 ± 1.0 vs. −1.9 ± 1.1), WOMAC (−15.1 ± 6.2 vs. −9.3 ± 5.9), and KSS (+18.7 ± 5.3 vs. +12.2 ± 5.6) compared to controls (all p < 0.001). A higher proportion of PRP-treated patients reported marked or complete symptom relief (62% vs. 39%) and better satisfaction scores (p < 0.001). Minor self-limiting adverse events (localized pain/swelling) were comparable between groups. Conclusion: This large-scale, randomized trial supports the therapeutic benefit of PRP in moderating pain and improving function in Grade II–III knee OA. Incorporating PRP into the multimodal management of moderate knee OA may offer enhanced symptom control and delay progression. Further research is warranted to determine optimal dosing protocols and long-term outcomes.